SARS-CoV-2: Pathogenesis, Molecular Targets and Experimental Models

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recent pandemic outbreak threatening human beings worldwide. This novel coronavirus disease-19 (COVID-19) infection causes severe morbidity and mortality and rapidly spreading across the countries. Therefore, there is an urgent need for basic fundamental research to understand the pathogenesis and druggable molecular targets of SARS-CoV-2. Recent sequencing data of the viral genome and X-ray crystallographic data of the viral proteins illustrate potential molecular targets that need to be investigated for structure-based drug design. Further, the SARS-CoV-2 viral pathogen isolated from clinical samples needs to be cultivated and titrated. All of these scenarios demand suitable laboratory experimental models. The experimental models should mimic the viral life cycle as it happens in the human lung epithelial cells. Recently, researchers employing primary human lung epithelial cells, intestinal epithelial cells, experimental cell lines like Vero cells, CaCo-2 cells, HEK-293, H1299, Calu-3 for understanding viral titer values. The human iPSC-derived lung organoids, small intestinal organoids, and blood vessel organoids increase interest among researchers to understand SARS-CoV-2 biology and treatment outcome. The SARS-CoV-2 enters the human lung epithelial cells using viral Spike (S1) protein and human angiotensin-converting enzyme 2 (ACE-2) receptor. The laboratory mouse show poor ACE-2 expression and thereby inefficient SARS-CoV-2 infection. Therefore, there was an urgent need to develop transgenic hACE-2 mouse models to understand antiviral agents' therapeutic outcomes. This review highlighted the viral pathogenesis, potential druggable molecular targets, and suitable experimental models for basic fundamental research.

Keywords: COVID-19; SARS-CoV-2; drug discovery; molecular targets; pathogenesis.

FIGURE 1

List of promising therapeutic candidates for SARS-CoV-2 infection. Remdesivir, ritonavir, and lopinavir were employed under emergency use of authorization. Anti-inflammatory drugs such as dexamethasone, hydroxychloroquine, rofecoxib were used to manage inflammatory responses during SARS-CoV-2 infection. Humanized monoclonal antibodies such as tocilizumab, sarilumab, eculizumab, casirivimab, and imdevimab were found to be effective against SARS-CoV-2 induced pneumonia.

FIGURE 2

3D Crystal structure of prominent molecular targets of SARS-CoV-2. The structures were obtained from the Protein Data Bank (PDB).

FIGURE 3

Mechanism of the pathogenesis of SARS-CoV-2 infection. (A) The TMPRSS2 process spike proteins for the binding with ACE-2 receptors present in the human epithelial cell membrane. (B) SARS-CoV-2 downregulates the expression of ACE-2 resulted in the upregulated expression pattern of Ang II. This Ang II binds with plasma membrane receptor AT1R and transduces signals to activate inflammatory transcription factors like NF-kB, STAT-3. These activated transcription factors are involved in the overexpression of several inflammatory. (C) The Ang II/AT1R interaction activates macrophages to produce excessive inflammatory cytokines that resulted in a “cytokine storm.”

FIGURE 4

Humanized monoclonal antibodies neutralize the SARS-CoV-2 virus, specifically targeting by attaching to the RBD domain of spike protein on the surface of the virus. (A) The SARS-CoV-2 binds through RBD of the S protein and ACE-2 receptor of the host cells. (B) Humanized monoclonal antibodies bind with the virus spike proteins and neutralize them.

FIGURE 5

Experimental models to study the pathogenesis of SARS-CoV-2 infection and study drug candidates’ pharmacological action.